This randomized phase II trial studies how well cabozantinib-s-malate works compared with temozolomide or dacarbazine in treating patients with melanoma of the eye (ocular melanoma). Cabozantinib-s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide and dacarbazine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether cabozantinib-s-malate works better than temozolomide or dacarbazine in treating patients with melanoma of the eye.

A patient will be declared a PFS4 success if they are on study and progression free for at least 4 months. This study will be declared promising if a one-sided chi-squared test for a difference in PFS4 rates yields a p-value of less than 0.10.

Secondary Outcome Measures:

Confirmed response rate as determined by the RECIST criteria (version 1.1) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]

The confirmed response rates will be estimated by dividing the number of confirmed responders by the number of evaluable patients. 95% confidence intervals will be calculated.

Maximum grade for each type of adverse event, graded according to the National Cancer Institute CTCAE version 4.0 [ Time Frame: Up to 2 years ] [ Designated as safety issue: Yes ]

Frequency tables will be created to look for patterns.

Overall survival (OS) [ Time Frame: Number of days from registration until death, assessed up to 2 years ] [ Designated as safety issue: No ]

The distribution of OS time will be estimated using the method of Kaplan Meier.

PFS [ Time Frame: Number of days from registration until disease progression (or death), assessed up to 2 years ] [ Designated as safety issue: No ]

The distribution of PFS time will be estimated using the method of Kaplan Meier.

Other Outcome Measures:

Expression of biomarkers [ Time Frame: Up to 4 months ] [ Designated as safety issue: No ]

Expression of epidermal growth factor receptor (EGFR), insulin-like growth factor-1 receptor (IGF-1R), vascular endothelial growth factor-receptor 2 (VEGF-R2), and Ki-67 in pre-treatment tissue will be explored in those patients treated with cabozantinib who have available tissue. Expression will be classified as positive (> 2+ immunohistochemistry) or negative. The proportions of patient's positive pre-treatment will be presented with 90% exact binomial confidence intervals. Pending adequate sample numbers, these findings will be correlated with clinical benefit using a Student's T-test.

Clinical benefit will be assessed according to RECIST criteria and dichotomized into clinical benefit (CR, PR or SD) or no clinical benefit (PD or non-evaluable). GNAQ/GNA11 expression will be classified as mutated or not. A Fisher's exact test will be utilized to determine any relationship here.

Clinical benefit will be assessed according to RECIST criteria and dichotomized into clinical benefit (complete response [CR], partial response [PR] or stable disease [SD]) or no clinical benefit (progressive disease [PD] or non-evaluable). Pre-treatment MET expression will be classified into positive or negative. A Fisher's exact test will be utilized to determine any relationship here.

Patients receive cabozantinib-s-malate PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Cabozantinib S-malate

Given PO

Other Names:

BMS-907351

Cabometyx

Cometriq

XL184

Other: Laboratory Biomarker Analysis

Correlative studies

Experimental: Arm II (temozolomide or dacarbazine)

Patients receive temozolomide PO daily on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. If temozolomide is not available, patients receive dacarbazine IV over 15-60 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. At the time of progression patients may cross-over to Arm I.

IV. Assess the safety of these agents by examining the toxicity profile. V. Correlate the response of mesenchymal-epithelial transition factor (MET) molecular status.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive cabozantinib-s-malate orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive temozolomide PO daily on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. If temozolomide is not available, patients receive dacarbazine intravenously (IV) over 15-60 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. At the time of progression patients may cross-over to Arm I.

After completion of study treatment, patients are followed up every 12 weeks for 2 years.

Eligibility

Ages Eligible for Study:

18 Years and older (Adult, Senior)

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Histologically or cytologically confirmed uveal melanoma that is metastatic or unresectable; if histologic or cytologic confirmation of the primary is not available, confirmation of the primary diagnosis of uveal melanoma by the treating investigator can be clinically obtained, as per standard practice for uveal melanoma; pathologic confirmation of diagnosis will be performed at the participating site

Measurable disease defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan or magnetic resonance imaging (MRI)

Prior systemic therapies allowed, except for those treatments directed toward, or with activity against, c-Met or vascular endothelial growth factor/receptor (VEGF/R), and the chemotherapy agents temozolomide and dacarbazine; prior treatment must have been no earlier than 3 weeks prior to starting treatment with cabozantinib with exceptions noted below and the following: at least 4 weeks since prior hepatic infusion or at least 2 weeks since radiation therapy

No cytotoxic chemotherapy including investigational cytotoxic chemotherapy or biologic agents (e.g., cytokines or antibodies) within the last 3 weeks, or nitrosoureas/mitomycin C within 6 weeks before the first dose of study treatment; at least 6 weeks must have elapsed if the last regimen included an anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) antibody; patients must have experienced disease progression on their prior therapy in the opinion of the treating investigator

No prior radiation therapy within the last 4 weeks, except as below

To the thoracic cavity, abdomen, or pelvis within 12 weeks before the first dose of study treatment, or has ongoing complications, or is without complete recovery to < grade 1 toxicity

To bone or brain metastasis within 14 days before the first dose of study treatment

To any other site(s) within 28 days before the first dose of study treatment

Prior radiation treatment may have included no more than 3000 centigray (cGy) to fields including substantial bone marrow

No prior radionuclide treatment within 6 weeks of the first dose of study treatment

No prior treatment with a small molecule kinase inhibitor or a hormonal therapy within 14 days or 5 half-lives (whichever is longer)

A corrected QT interval calculated by the Fridericia formula (QTcF) =< 500 ms within 28 days before randomization; Note: if initial QTcF is found to be > 500 ms, two additional electrocardiograms (EKGs) separated by at least 3 minutes should be performed; if the average of these three consecutive results for QTcF is =< 500 ms, the patient meets eligibility in this regard

Common Terminology Criteria for Adverse Events (CTCAE) recovered to baseline or CTCAE =< grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant adverse events (AEs)

No active brain metastases or epidural disease; patients with brain metastases previously treated with whole brain radiation or radiosurgery or patients with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 12 weeks before starting study treatment; baseline brain imaging with contrast-enhanced CT or MRI scans for patients with known brain metastases is required to confirm eligibility

No clinically significant gastrointestinal bleeding within 24 weeks before the first dose of study treatment

No hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood within 12 weeks before the first dose of study treatment

No signs indicative of pulmonary hemorrhage within 12 weeks before the first dose of study treatment

No prior radiographic evidence of cavitating pulmonary lesion(s)

No tumor in contact with, invading or encasing any major blood vessels

No evidence of tumor invading the gastrointestinal (GI) tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of treatment

The patient may not have uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:

Cardiovascular disorders including:

Congestive heart failure (CHF): New York Heart Association (NYHA) class III (moderate) or class IV (severe) at the time of screening

Any of the following within 24 weeks before the first dose of study treatment:

Abdominal fistula

Gastrointestinal perforation

Intra-abdominal abscess; Note: complete resolution of an intra-abdominal abscess must be confirmed prior to initiating treatment with cabozantinib even if the abscess occurred more that 24 weeks before the first dose of study treatment

Bowel obstruction or gastric outlet obstruction

Other clinically significant disorders such as:

Serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment

History of organ transplant

Concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment

History of major surgery as follows:

Major surgery in past 8 weeks of the first dose of cabozantinib if there were no wound healing complications or within 24 weeks of the first dose of cabozantinib if there were wound complications

Minor surgery within 4 weeks of the first dose of cabozantinib if there were no wound healing complications or within 12 weeks of the first dose of cabozantinib if there were wound complications

In addition, complete wound healing from prior surgery must be confirmed at least 28 days before the first dose of cabozantinib irrespective of the time from surgery

Active infection requiring systemic treatment within 28 days before the first dose of study treatment

No concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or factor Xa inhibitors, or antiplatelet agents (e.g., clopidogrel); low dose aspirin (=< 81 mg/day), low-dose warfarin (=< 1 mg/day), and prophylactic low molecular weight heparin (LMWH) are permitted; please note that drugs that strongly induce or inhibit cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) or are associated with a risk of Torsades are not allowed; chronic concomitant treatment of CYP3A4 inducers is not allowed (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's wort); as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product; the following drugs are strong inhibitors of CYP3A4 and are not allowed during the treatment with cabozantinib:

Boceprevir

Indinavir

Nelfinavir

Lopinavir/ritonavir

Saquinavir

Telaprevir

Ritonavir

Clarithromycin

Conivaptan

Itraconazole

Ketoconazole

Mibefradil

Nefazodone

Posaconazole

Voriconazole

Telithromycin

Drugs with possible or conditional risk of torsades should be used with caution knowing that cabozantinib could prolong the QT interval

Patients who are pregnant or nursing are not eligible; women of child bearing potential must have a negative serum or urine pregnancy test within 16 days prior to registration; women of child-bearing potential include:

Any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea >= 12 consecutive months)

Women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (e.g., vasectomy)

No history of allergic reactions attributed to compounds of similar chemical or biologic composition to cabozantinib, temozolomide and dacarbazine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
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For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01835145